Venous thromboembolism is a general term referring to thrombus generated in vena, comprising pulmonary embolism (PE) and deep venous thrombosis (DVT), wherein PE comprises acute pulmonary embolism (APE), and chronic thromboembolic pulmonary hypertension (CTEPH). VTE is a frequently-occurring disease, wherein PE has become a worldwide health care problem due to its high morbidity rate, high misdiagnosis rate, and high mortality rate (Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int. Angiol. 2006; 25(2): 101-161).
According to the traditional phlebothrombosis theory, in the state when the blood flow is slow, the endothelial cells in veins are injured or the coagulation factors are hyperfunctional, the injured endothelial cells and platelets are activated, the functions of coagulation factors are activated, and thereby venous thrombus is generated. The thrombus generated in veins are rich in fibrins and erythrocytes, and merely contain a little amount of platelets (Furie, Bruce; Furie, Barbara, Mechanisms of Thrombus Formation, The New England Journal of Medicine 2008; 359 (9): 938-949).
The recent research results of the present inventor indicate that, the protein compositions in APE thrombus are mainly composed of fibrinogens, wherein there are a little amount of serum proteins and cytoskeletal proteins (Wang L, Gong Z, Jiang J, Xu W, Duan Q, Liu J, et al. Confusion of Wide Thrombolytic Time Window for Acute Pulmonary Embolism: Mass Spectrographic Analysis for Thrombus Proteins. Am. J. Respir Crit. Care Med. 2011 184: 145-146). Such a discovery changes the traditional view that venous thrombus proteins are mainly fibrins, providing a novel way for diagnosing and treating VTE. For example, investigations for the binding manners between the fibrinogens in VTE thrombus and the leukocytes, platelets and erythrocytes in thrombus can provide information concerning the mechanism of venous thrombus formation.
Integrin is a type of receptor protein that mediates the attachments between cells, and between a cell and its surrounding tissues (such as other cells or extracellular matrix). It also plays an important role in cell signaling, and thereby mediates information exchange between a cell and its surrounding environments, allowing the cell to make rapid response to changes in the environments (e.g. allowing the blood to coagulate through platelets) (Hynes R, Integrins: bidirectional, allosteric signaling machines. Cell (2002), 110 (6): 673-87).
Integrin is a heterodimer, and it contains two different chains, termed as a subunit and β subunit, respectively. Currently 18 α subunits and 9 β subunits have been identified in mammal integrins, and more than 20 integrins can be formed through respective combinations of these subunits (Humphries M J. Integrin structure. Biochem Soc Trans. 2000; 28(4): 311-39). These more than 20 integrins form an integrin family, wherein integrins containing the same β subunit form integrin β subfamily. For example, the integrin β1-3 subunits encoded by ITGB1, ITGB2, and ITGB3 genes are ITGB1 (also called CD29), ITGB2 (also called CD18), and ITGB3 (also called CD61), respectively. The integrin β1 subfamily containing ITGB1 subunit is widely distributed, and mainly mediates the attachments between a cell and the extracellular matrix compositions, and mediates lymphocyte homing as well as the adhesion between leukocytes and activated endothelial cells; β1 subfamily is mainly distributed on membrane surfaces of activated lymphocytes and platelets (Billard M J, McIntyre B W. CD45RA T-cell activation without proliferation by a partial agonist monoclonal antibody to beta1 integrin. Immunol Cell Biol. 2008 May-June; 86(4): 381-4). The subfamily containing integrin β2 is mainly found on the surfaces of various leukocytes, which is used for mediating interactions between cells, and which is mainly distributed in neutrophile granulocytes and monocytes (Fu C, Tong C, Wang M, Gao Y, Zhang Y, Lü S, Liang S, Dong C, Long M. Determining beta2-integrin and intercellular adhesion molecule 1 binding kinetics in tumor cell adhesion to leukocytes and endothelial cells by a gas-driven micropipette assay. J Biol Chem. 2011 Oct. 7; 286(40): 34777-87). The subfamily containing integrin β3 is mainly distributed on the surfaces of platelets, which mediates the aggregation of platelets, and involves in the formation of thrombus (Sachs U J, Bakchoul T, Eva O, Giptner A, Bein G, Aster R H, Gitter M, Peterson J, Santoso S. A point mutation in EGF-4 domain of β3 integrin is responsible for the formation of the Seca platelet alloantigen and affects receptor function. Thromb Haemost. 2011; 107(1)).